The home side will enter the match off the back of a 1-1 draw with Wolverhampton Wanderers in the league on Friday, while Leeds recorded a huge 1-0 victory over Southampton on Saturday afternoon.
Match preview
Fulham stretched their unbeaten run to six matches when they came from behind to draw 1-1 with Wolves in the league on Friday night; Pablo Sarabia sent the visitors ahead in the first half, but Marco Silva's side secured a share of the spoils courtesy of Manor Solomon's third goal in as many matches.
The result has left the Cottagers in sixth position in the table, just three points behind fourth-placed Tottenham Hotspur, with the team enjoying a brilliant campaign thus far.
Fulham's focus is undoubtedly the Premier League, and it would be some story if Silva could lead the team to a European finish, but they also have the chance to reach the quarter-finals of the FA Cup.
The West London club have never won the FA Cup, with their best performance in the competition coming in 1974-75, when they reached the final before losing to West Ham United.
Fulham have already beaten Leeds this season, recording a 3-2 victory in the Premier League back in October, which ended a run of four straight losses to the Whites in all competitions.
Leeds, meanwhile, will enter this match off the back of a 1-0 victory over Southampton, with Junior Firpo netting the only goal of the contest to secure a vital three points in Javi Gracia's first game at the helm.
The result moved the team out of the relegation zone and into 17th, but they are just one point clear of 18th-placed Everton and still face a huge battle to stay in England's top flight this term.
Leeds have overcome Cardiff City and Accrington Stanley to reach this round of the FA Cup, while Fulham have beaten Hull City and Sunderland.
Unlike Fulham, though, the Whites have previously won the FA Cup, lifting the trophy in 1972 by recording a 1-0 victory over Arsenal in the final, with Allan Clarke netting the only goal of the contest.
Gracia has been brought to the club to keep them in the Premier League this season, but the team are just one win away from the final eight of a major cup competition, and the match could provide opportunities for a number of players looking to impress their new head coach.
Fulham FA Cup form:
W
D
W
Fulham form (all competitions):
D
D
W
W
W
D
Leeds United FA Cup form:
D
W
W
Leeds United form (all competitions):
W
L
D
L
L
W
Team News
Fulham will again be without the services of Tom Cairney and Neeskens Kebano through injury, while leading goalscorer Aleksandar Mitrovic remains a doubt due to a thigh problem.
Silva will not want to take any risks with Mitrovic, so it would not be a surprise to see him sit this one out also with a view to returning against Brentford in the league on March 6.
There will be changes from the side that started against Wolves in the Premier League, with Shane Duffy, Tosin Adarabioyo, Harry Wilson and Layvin Kurzawa all expected to feature in the XI, while there should be a spot between the sticks for Marek Rodak.
As for Leeds, Rodrigo, Archie Gray, Adam Forshaw and Stuart Dallas are definitely out, while Luis Sinisterra and Pascal Struijk remain injury doubts.
There will also be plenty of changes from the team's Premier League match on Saturday, with Marc Roca, Sam Greenwood, Joel Robles and Rasmus Kristensen all pushing to come into the XI.
Georginio Rutter could also come in alongside Patrick Bamford in the final third of the field, while there might be a position in central midfield for teenager Darko Gyabi.
Fulham possible starting lineup:
Rodak; Cedric, Duffy, Adarabioyo, Kurzawa; Lukic, Reed; Wilson, Solomon, James; Vinicius
Leeds United possible starting lineup:
Robles; Kristensen, Koch, Wober, Firpo; Greenwood, Gyabi, Roca, Summerville; Bamford, Rutter
We say: Fulham 2-1 Leeds United
This has all of the makings of a very entertaining match, but it is difficult to know exactly what to expect when two Premier League sides meet at this stage of the FA Cup. Both managers will make changes, but Fulham's squad is arguably stronger, so we are backing the home side to secure a spot in the next round.